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Testoderm

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CLINICAL PHARMACOLOGY

Testosterone

The TESTODERM (testosterone (transdermal)) ® products deliver physiologic amounts of testosterone, the primary endogenous androgenic hormone. Endogenous testosterone serum concentrations in normal males follow a circadian pattern. Daily morning application of any of the TESTODERM (testosterone (transdermal)) ® products results in a serum testosterone profile that approximates the natural endogenous pattern of normal men.

General Androgen Effects

Endogenous androgens, including testosterone and dihydrotesterone (DHT), are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of prostate, seminal vesicles, penis, and scrotum; the development of male hair distribution, such as facial, pubic, chest, and axillary hair; laryngeal enlargement, vocal chord thickening, alterations in body musculature, and fat distribution. DHT is necessary for the normal development of secondary sex characteristics.

Male hypogonadism results from insufficient secretion of testosterone and is characterized by low serum testosterone concentrations. Symptoms associated with male hypogonadism include impotence and decreased sexual desire, fatigue and loss of energy, mood depression, and regression of secondary sexual characteristics.

Drugs in the androgen class also cause retention of nitrogen, sodium, potassium, phosphorus, and decreased urinary excretion of calcium. Androgens have been reported to increase protein anabolism and decrease protein catabolism. Nitrogen balance is improved only when there is sufficient intake of calories and protein.

Androgens are responsible for the growth spurt of adolescence and for the eventual termination of linear growth brought about by fusion of the epiphyseal growth centers. In children, exogenous androgens accelerate linear growth rates but may cause a disproportionate advancement in bone maturation. Use over long periods may result in fusion of the epiphyseal growth centers and termination of the growth process. Androgens have been reported to stimulate the production of red blood cells by enhancing the production of erythropoietin.

During exogenous administration of androgens, endogenous testosterone release may be inhibited through feedback inhibition of pituitary luteinizing hormone (LH). At large does of exogenous androgens, spermatogenesis may also be suppressed through feedback inhibition of pituitary follicle-stimulating hormone (FSH).

There is a lack of substantial evidence that androgens are effective in accelerating fracture healing or in shortening post-surgical convalescence.

Pharmacokinetics

Absorption

Daily morning application of any of the TESTODERM (testosterone (transdermal)) ® products approximates the natural endogenous pattern of serum testosterone of normal males. Following application, testosterone is continuously absorbed during the 24-hour dosing period. The serum testosterone concentration rises to a maximum at 2 to 4 hours and return toward baseline within approximately 2 hours after system removal. The testosterone levels achieved with TESTODERM (testosterone (transdermal)) ® products generally are within the range for normal men. Patients vary in their ability to absorb testosterone transdermally (see Clinical Studies).

TESTODERM (testosterone (transdermal)) ® TTS
For TESTODERM (testosterone (transdermal)) ® TTS three skin sites (arm, back, and upper buttocks), representing recommended application sites, are interchangeable based on equivalent testosterone AUC (0-27) (area under serum concentration curve) values.

In clinical trials, 94% of patients on TESTODERM (testosterone (transdermal)) TTS treatment achieved maximum and average serum testosterone concentrations (Cmax and Cavg, respectively) within the normal range; the average Cmax and Cavg serum testosterone concentrations were 531 ng/dL and 366 ng/dL, respectively. Within-subject coefficient of variation in testosterone Cavg for subjects on TESTODERM (testosterone (transdermal)) TTS therapy was 17%.

The typical steady state serum testosterone concentration pattern achieved with a nominal testosterone dose of 5 mg/day from TESTODERM (testosterone (transdermal)) TTS is shown in Figure 1.

Figure 1. Serum concentrations of testosterone (mean ± SD) during pretreatment baseline or while wearing a TESTODERM (testosterone (transdermal)) TTS system on the upper buttocks (n=32). Systems were applied at 0 hours (8 AM) and removed 24 hours later.
Normal range serum testosterone concentrations are reached during the first day of dosing.
There is no accumulation of testosterone following repeated application of TESTODERM (testosterone (transdermal)) TTS.
Two TESTODERM (testosterone (transdermal)) TTS systems deliver a testosterone dose which is twice that delivered by a single system.
There is no first-pass skin metabolism of testosterone to DHT when applied to arm, back or upper buttocks skin sites as recommended.

TESTODERM (testosterone (transdermal))
Scrotal skin is at least five times more permeable to testosterone than other skin sites. TESTODERM (testosterone (transdermal)) or TESTODERM (testosterone (transdermal)) WITH ADHESIVE will not produce adequate serum testosterone concentrations if applied to non-scrotal skin.

Hypogonadal men using TESTODERM (testosterone (transdermal)) therapy have trough serum testosterone concentrations that are about 15% of peak levels. Serum levels reach a plateau at 3 to 4 weeks.

TESTODERM (testosterone (transdermal)) WITH ADHESIVE
Data from a pharmacokinetic trial in 50 normal male subjects show that TESTODERM (testosterone (transdermal)) WITH ADHESIVE applied to scrotal skin is equivalent to TESTODERM (testosterone (transdermal)) with respect to rate (Cmax) and extent (AUC) of testosterone delivery.

Distribution

Circulating testosterone is chiefly bound in the serum to sex hormone-binding globulin (SHBG) and albumin. The albumin-bound fraction of testosterone easily dissociates from albumin and is presumed to be bioactive. The portion of testosterone bound to SHBG is not considered biologically active. The amount of SHBG in the serum and the total testosterone level will determine the distribution of bioactive and nonbioactive androgen. SHBG-binding capacity is high in prepubertal children, declines during puberty and adulthood, and increases again during the later decades of life.

Metabolism

There is considerable variation in the half-life of testosterone as reported in the literature, ranging from 10 to 100 minutes. Testosterone is a substrate for conversion to an active metabolite, dihydrotestosterone (DHT). Testosterone is metabolized to various 17-keto steroids through two different pathways, and the major active metabolites are estradiol and DHT. Concentrations of estradiol in normal men are 1.0 to 5.0 ng/dL. DHT concentrations in normal male serum are 30 to 85 ng/dL. DHT binds with greater affinity to SHBG than does testosterone. In many tissues the activity of testosterone appears to depend on reduction to DHT, which binds to cytosol receptor proteins. The steroid-receptor complex is transported to the nucleus where it initiates transcription and cellular changes related to androgen action. In reproductive tissues, DHT is further metabolized to 3-alpha and 3-beta androstanediol.

Composite results of all studies with TESTODERM (testosterone (transdermal)) show elevated DHT concentrations and a change in the ratio of testosterone to DHT (T/DHT) during treatment. The range in this ratio was 0.7 - 12.5, as compared with a ratio of 3.6 - 15.2 in normal untreated men. The long-term effects of the change in this ratio are not known.

The T/DHT ratio during TESTODERM (testosterone (transdermal)) TTS treatment was not statistically significantly different from placebo treatment.

Excretion

About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver.

Special Populations

Geriatric

In clinical trials with TESTODERM (testosterone (transdermal)) TTS, Cavg testosterone concentrations were not different between men aged 65 and older and younger adult males.

Race

There is insufficient information available from trials with the TESTODERM (testosterone (transdermal)) products to compare testosterone pharmacokinetics in different racial groups.

Renal Insufficiency

There is no experience with the use of the TESTODERM (testosterone (transdermal)) products in patients with renal insufficiency.

Hepatic Insufficiency

There is no experience with the use of the TESTODERM (testosterone (transdermal)) products in patients with hepatic insufficiency.

Drug-Drug Interactions

See PRECAUTIONS: Drug Interactions.

Clinical Studies

TESTODERM (testosterone (transdermal)) TTS
Of 32 hypogonadal men receiving daily application of a single TESTODERM (testosterone (transdermal)) TTS system, 94% achieved normal serum concentrations of testosterone as determined by Cmax and Cavg (200-1000 ng/dL). Mean free testosterone, estradiol, and dihydrotestosterone concentrations were also in the normal range after application of TESTODERM (testosterone (transdermal)) TTS.

TESTODERM (testosterone (transdermal)) and TESTODERM (testosterone (transdermal)) WITH ADHESIVE
After at least 3 weeks of TESTODERM (testosterone (transdermal)) therapy when steady-state is obtained, 30 hypogonadal men treated with 6 mg/d systems for 22 hours daily achieved mean maximum serum testosterone concentrations of 593 ng/dL at 2 to 4 hours post application. Sixty percent of the patients achieved individual maximal testosterone concentrations >500 ng/dL. The mean 24 hour steady-state AUC (area under the curve) value was 9132 ng/dL. The mean DHT serum concentrations ranged from 134 to 162 ng/dL. Normal levels of testosterone have been maintained in patients who have worn the systems for up to six years. DHT levels also remain stable. The increase in serum testosterone concentration is proportional to the size of the system.

The variability of total testosterone concentrations among patients receiving TESTODERM (testosterone (transdermal)) treatment was 35% to 49%. The coefficient of variation of total testosterone concentrations within individual patients was 30% to 41%. This variability is comparable to the values reported in the literature for both normal and hypogonadal men.

In two 12-week clinical studies in 72 hypogonadal men, TESTODERM (testosterone (transdermal)) therapy produced positive effects on mood and sexual behavior. By five weeks, 45 patients not previously treated with TESTODERM (testosterone (transdermal)) showed statistically significant increases in sexual activity. Compared to baseline, mean sexual events per week increased for sexual intercourse (0.3 to 0.8), orgasm (0.4 to 1.2), waking erections (1.0 to 3.5), and spontaneous erections (0.4 to 2.8).

Changes in nonfasting serum lipid concentrations were observed during TESTODERM (testosterone (transdermal)) therapy. By three months total cholesterol and high-density lipoprotein cholesterol decreased an average of 8% and 13%, respectively. High-density lipoprotein cholesterol remained stable thereafter. Total cholesterol continued to decrease through two years. At the end of two years, the total cholesterol/high-density lipoprotein cholesterol ratio was not different from pretreatment values.

Estradiol levels increased to the normal range with treatment. Sporadic elevations of estradiol above the normal range for men were observed in 3 of 72 patients and these were not associated with feminizing side effects.

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.

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